Cyanoguanidine derivatives

ABSTRACT

Novel cyanoguanidine derivatives, and acid addition salts thereof useful as medicines which have pharmacological actions such as anti-secretory effect, local anesthesia action and the like; and process for the preparation thereof.

This invention relates to novel cyanoguanidine derivatives, acid addition salts thereof having excellent actions as medicines and to the process for the preparation thereof, wherein the cyanoguanidine derivatives are represented by the general formula: ##STR1## wherein A represents a substituted or unsubstituted phenyl, furyl, thienyl or cycloalkyl group;

B represents pyridyl, phenyl, or pyridine-N-oxide group;

R represents a lower alkyl group, a lower alkenyl group, or a group of the formula: ##STR2## wherein R₁ and R₂ are the same or different, and each represent a lower alkyl group, or together form nitrogen-containing heterocycle with the nitrogen atom to which they bond, and n is an integer of 1-3, or R represents a group of the formula: ##STR3## wherein R₃ is a lower alkyl group, n is an integer of 1-3 and m is an integer of 4-5;

X represents an alkylene or an alkylene group containing the terminal sulfur atom; and

p is 0 or 1, with the proviso that (i) when A is unsubstituted phenyl and B is pyridyl, p is 1 and R is a group of the formula: ##STR4## or a group of the formula: ##STR5## and (ii) when A is unsubstituted phenyl and B is phenyl or pyridine-N-oxide, p is 0; and intermediates therefor represented by the general formula: ##STR6## wherein Y represents a lower alkoxy or a lower alkylthio group, and A, B, X and p have the same meanings as defined above.

Illustrative substituents on the substituted phenyl groups mentioned for the definition of A in the general formula (I) include, practically, a lower alkyl, lower alkenyl, halogen, lower alkoxy, lower alkylthio, lower alkylsulfonyl, halogen substituted lower alkyl groups and the like. The term "lower" used in the above illustration is meant for any straight or branched carbon chains containing 1-6 carbon atoms. Illustrative said lower alkyl groups may include, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl and the like, and lower alkenyl groups may include isopropenyl, allyl, crotyl, methallyl and the like.

The lower alkoxy or a lower alkylthio group mentioned for the definition of Y in the general formula (V) has also 1-6 carbon atoms.

The term "halogen" means practically fluoro, chloro, iodo or bromo group.

The cycloalkyl group means practically a cycloalkyl group containing 5-6 carbon atoms. The lower alkyl and lower alkenyl groups shown in the definitions of R, R₁ and R₂ have the same meanings as those defined above.

Further, illustrative nitrogen-containing heterocycles formed by the groups R₁ and R₂, with nitrogen atom to which they bond, include, for example, pyrrolidine, piperidine, piperazine, morpholine and the like.

Alkylene represented by X means lower alkylene groups, such, for example, as methylene, ethylene, propylene, and the like, which may contain a terminal sulfur atom. The pyridyl group represented by B may be combined at any one of the 2, 3 and 4 positions on the pyridine ring.

There are some tautomers of the compound (I) of this invention, and these tautomers are, of course, included in this invention.

The compound (I) of this invention may be easily converted into the pharmacologically acceptable acid addition salt by reacting it with an inorganic or organic acid. Illustrative inorganic acids include hydrochloric, hydrobromic, hydroiodic, sulfuric acids and the like, and illustrative organic acids include maleic, fumaric, succinic, acetic, malonic, citric, benzoic acids and the like.

The compounds to be provided according to this invention are all novel compounds which have not as yet been reported in the literature. Said compounds have very excellent and broad pharmacological actions as medicine, such as, very intensively, gastric juice secretion inhibitory or antisecretory, antidepressant, local anesthesia, antidiarrheal, antiedema, diuretic, hypertensive, hypotensive, vasoconstrictive, antiserotonin, smooth muscle relaxing, coronary vasodilative, and bradycardia actions and the like. Thus, the compounds (I) of this invention are useful as various medicines due to such pharmacological actions. Illustrative medicines include antipeptic ulcer drug, antidepressant, local anesthetics, anti-inflammatory agents, diuretics, antiallergic agents, antidiarrheal, hypertensive, hypotensive, anti-arrhythmic agent, muscle relaxants, coronary vasodilator and the like.

Since the inhibitory action of the compounds according to this invention to gastric juice secretion is not based on the anticholine action, the compound of this invention do not exhibit the side effect due to the anticholine action. This is a great characteristic of the compounds according to this invention, and therefore the compounds are particularly expected as a new type antipeptic ulcer drug among the various medicines mentioned above.

The compounds (I) of this invention can be prepared through various processes. Among these processes, the following shows one process which may be usually employed. ##STR7## wherein Y represents a lower alkoxy or a lower alkylthio group, and A, B, R, X and p have the same meanings as defined above.

PROCESS (1) FOR THE PREPARATION

The compounds (I) of this invention are produced, in one step, by reacting the amine derivative represented by the above formula (II) with an isothiourea derivative or an isourea derivative represented by the above formula (III). This reaction may be effected in the presence or absence of solvent.

An excess amount of the amine derivative may be used as a solvent. However, it is desirable to use, for example, methanol, ethanol, isopropanol, acetonitrile, chloroform and the like as solvent. The reaction is effected at room temperature or elevated temperature. The reaction may be effected under reflux, when solvent is used.

PROCESS (2) FOR THE PREPARATION

The compounds represented by the general formula (I) of this invention are produced, through two steps, by reacting the amine derivative represented by the general formula (II) with a compound represented by the general formula (IV) to produce a compound represented by the general formula (V), followed by reacting the latter compound (V) with an amine represented by the general formula (VI). According to this process, both reactions of said two steps may be effected with the similar procedures as the reaction between the amine derivative (II) and the isothiourea derivative or isourea derivative (III) as described above. This reaction may be also effected without separating the compound (V) from the reaction vessel after the reaction of the amine derivative (II) with the compound (IV).

The excellent pharmacological actions of the compounds of this invention are illustrated hereinafter with respect to typical compounds of this invention.

1. Anti-secretory effect

Inhibitory ratio to the gastric juice serection was determined by the Shay rat 4 hr method [H. Shay et al.; Gastroentrogy, vol. 5, P. 43 (1945)]. Results are shown in Table 1.

                  TABLE 1                                                          ______________________________________                                                             Oral dosage                                                                               Inhibitory                                      Compound            (mg/kg)    ratio (%)                                       ______________________________________                                         Knpwn   Cimetidine                                                             compound                                                                               (control)       50         85.8                                                N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)benzyl]                                                    guanidine (control)                                                                            100        69.3                                        Compound                                                                               N-cyano-N'-ethyl-N-                                                    of this [α-(2-pyridyl)ortho-                                             invention                                                                              methylbenzyl]                                                                  guanidine       50         93.5                                                N-cyano-N'-allyl-N-                                                            [α-(2-pyridyl)ortho-                                                     methylbenzyl]                                                                  guanidine       50         79.0                                                N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)ortho-                                                     methoxybenzyl]                                                                 guanidine       50         91.6                                                N-cyano-N'-ethyl-N-                                                            [α-(2-pyridyl)ortho-                                                     methoxybenzyl]                                                                 guanidine       50         96.7                                                N-cyano-N'-ethyl-N-                                                            [α-(2-pyridyl)metha-                                                     chlorobenzyl]                                                                  guanidine       50         79.2                                                N-cyano-N'-(3-diethyl-                                                         aminopropyl)-N-[α-(2-                                                    pyridyl)benzyl                                                                 guanidine       100        81.0                                                N-cyano-N'-(1-ethyl                                                            pyrrolyl-2-)-methyl-N-                                                         [α-(2-pyridyl)benzyl]                                                    guanidine       100        86.0                                        ______________________________________                                    

2. Anti-depressant efficacy

Anti-depressant efficacy was determined using mouse by the method as described in G. Chen and B. Bohner: J. Pharmac. Exptl. Therap. 131, 179 (1961).

Results are shown in Table 2.

                  TABLE 2                                                          ______________________________________                                                                Minimum effective                                                              dose (mouse, oral                                               Compound       dosage mg/kg)                                           ______________________________________                                         Known     Imipramine                                                           compound  (control)        10                                                            N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)benzyl]                                                    guanidine (control)                                                                             25                                                  Compound  N-cyano-N'-ethyl-N-                                                  of this   [α-(2-pyridyl)ortho-                                           invention methylbenzyl]                                                                  guanidine        1                                                             N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)metha-                                                     methylbenzyl]                                                                  guanidine        10                                                            N-cyano-N'-ethyl-N-                                                            [α(2-pyridyl)ortho- -                                                                     methoxybenzyl]                                                guanidine        10                                                            N-cyano-N'-ethyl-N-                                                            [α-(2-pyridyl)ortho-                                                     chlorobenzyl]                                                                  guanidine        10                                                            N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)metha-                                                     chlorobenzyl]                                                                  guanidine        2.5                                                 ______________________________________                                    

3. Local anesthesia action

Local anesthesia action was determined by the method as described in M. R. A. Chance et al., J. Pharmac. Exptl. Therap. 82, 203 (1944). Results are shown in Table 3.

                  TABLE 3                                                          ______________________________________                                                                Minimum effective                                              Compound        concentration (%)                                       ______________________________________                                         Known    Dibucaine                                                             compound (control)         0.1                                                          N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)benzyl]                                                    guanidine (control)                                                                              >3                                                  Compound N-cyano-N'-(1-ethyl-                                                  of this  pyrolidyl-2)methyl-N-                                                 invention                                                                               [α-(2-pyridyl)para-                                                      methylbenzyl]                                                                  guanidine         0.5                                                          N-cyano-N'-(3-dimethyl-                                                        aminopropyl)-N-[α-(2-                                                    pyridyl)paramethylbenzyl]                                                      guanidine         0.5                                                          N-cyano-N'-(1-ethylpyro-                                                       lidyl-2)methyl-N-[α-(2-                                                  pyridyl)orthomethoxy-                                                          benzyl]guanidine  0.25                                                ______________________________________                                    

4. Antidiarrheal action

                  TABLE 4                                                          ______________________________________                                                                Minimum effective                                                              dose (mouse, oral                                               Compound       dosage, mg/Kg)                                          ______________________________________                                         Known     Atropine                                                             compound  (control)        60                                                            N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)benzyl]                                                    guanidine (control)                                                                             50                                                  Compound  N-cyano-N'-ethyl-N-                                                  of this   [α-(2-pyridyl)ortho-                                           invention methylbenzyl]                                                                  guanidine         1                                                            N-cyano-N'-allyl-N-                                                            [α-(2-pyridyl)ortho-                                                     methylbenzyl]                                                                  guanidine        10                                                            N-cyano-N'-ethyl-N-                                                            [α-(2-pyridyl)ortho-                                                     chlorobenzyl]                                                                  guanidine         5                                                            N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)metha-                                                     chlorobenzyl]                                                                  guanidine        10                                                            N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)metha-                                                     trifluoromethylbenzyl]                                                         guanidine        25                                                  ______________________________________                                    

5. Antiedema action

Antiedema action was determined using rat by the method as described C. A. Winter et al.: Proc. Soc. Exp. Biol. Med. 111, 544 (1962). Results are shown in Table 5.

                  TABLE 5                                                          ______________________________________                                                                Minimum effective                                                              dose (rat, oral                                                 Compound       dosage, mg/Kg)                                          ______________________________________                                         Known     Indomethacin                                                         compound  (control)        4.0                                                           N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)benzyl]                                                    guanidine (control)                                                                             >100                                                Compound  N-cyano-N'-methyl-N-                                                 of this   [α-(2-pyridyl)ortho-                                           invention methylbenzyl]                                                                  guanidine        2.5                                                           N-cyano-N'-ethyl-N-                                                            [α-(2-pyridyl)ortho-                                                     methylbenzyl]                                                                  guanidine        2.5                                                           N-cyano-N'-ethyl-N-                                                            [α-(2-pyridyl)ortho-                                                     methoxybenzyl]                                                                 guanidine        2.5                                                 ______________________________________                                    

6. Diuretics action

Diuretics action was determined by the method as described in E. Cornish: J. Pharm. Pharmacol. 18, 65 (1966). Results are shown in Table 6.

                  TABLE 6                                                          ______________________________________                                                                Minimum effective                                                              dose (oral dosage                                               Compound       mg/Kg)                                                  ______________________________________                                         Known     Hydrofulumethiazide                                                  compound  (control)        2.0                                                           N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)benzyl]                                                    guanidine (control)                                                                             5.0                                                 Compound  N-cyano-N'-ethyl-N-                                                  of this   [α-(2-pyridyl)ortho-                                           invention methylbenzyl]                                                                  guanidine        0.1                                                           N-cyano-N'-ethyl-N-                                                            [α-(2-pyridyl)metha-                                                     methylbenzyl]                                                                  guanidine         0.25                                                         N-cyano-N'-ethyl-N-                                                            [α-(2-pyridyl)metha-                                                     chlorobenzyl]                                                                  guanidine        0.5                                                           N-cyano-N'-methyl-N-                                                           [α-(2-pyridyl)metha-                                                     trifluoromethylbenzyl]                                                         guanidine        0.5                                                           N-cyano-N'-allyl-N-                                                            [α-(2-pyridyl)ortho-                                                     methoxybenzyl]                                                                 guanidine        1.0                                                 ______________________________________                                    

As apparently seen from the results of the above pharmacological experiments, the guanidine derivatives provided according to this invention exhibit very intense pharmacological actions, as compared with the known compounds.

This invention will be more particularly illustrated by the following examples. However, it should be understood that this invention is not limited to only those examples.

EXAMPLE 1 N-cyano-N'-methyl-N-[α-(2-pyridyl)-o-methylbenzyl]guanidine

(1) (a) Dimethylcyanodithioimido carbonate in amount of 11.4 g (0.1 mol) and α-(2-pyridyl)-o-methylbenzylamine in amount of 18.4 g (0.1 mol) were dissolved in 300 ml of ethanol. The whole was allowed to react at room temperature overnight. Crystals deposited were separated by filtration. The filtrate was concentrated to deposit an additional amount of crystals. These crystals were combined and recrystallized from ethyl acetate to produce 17.7 g (yield: 66.4%) of N-cyano-S-methyl-N-[α-(2-pyridyl)orthomethylbenzyl]isothiourea.

Melting point: 162°-4° C.

Elementary analysis of the compound having the presumed formula C₁₆ H₁₆ N₄ S gave:

    ______________________________________                                                    C          H      N                                                 ______________________________________                                         Calculated                                                                               (%):   64.83        5.44 18.90                                       Found     (%):   65.03        5.31 18.79                                       ______________________________________                                    

(b) A mixture consisting of 5.9 g (0.02 mol) of N-cyano-S-methyl-N-[α-(2-pyridyl)orthomethylbenzyl]isothiourea prepared in (a), 30 ml of 20% solution of methylamine in ethanol and 70 ml of ethanol was prepared and reacted at room temperature overnight. The reaction solution was concentrated under a reduced pressure. The residue was recrystallized from ethyl acetate to produce 4.7 g of the subject material, N-cyano-N'-methyl-N-[α-(2-pyridyl)orthomethylbenzyl]guanidine (yield: 85.0%).

Melting point: 187°-9° C.

Elementary analysis of the compound having the presumed formula C₁₆ H₁₇ N₅ gave:

    ______________________________________                                                    C          H      N                                                 ______________________________________                                         Calculated                                                                               (%):   68.78        6.13 25.07                                       Found     (%):   68.83        6.01 25.26                                       ______________________________________                                    

(2) Alpha-(2-pyridyl)orthomethylbenzylamine in amount of 1.8 g (0.01 mol) and N-cyano-S,N'-dimethylisothiourea in amount of 1.3 g (0.01 mol) were dissolved in 50 ml of acetonitrile. The whole was reacted under heating for 10-15 hours. The reaction solution was then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to produce 1.6 g of the subject material, N-cyano-N'-methyl-N-[α-(2-pyridyl)orthomethylbenzyl]guanidine (yield: 59.0%).

Melting point: 187°-9° C.

Elementary analysis of the compound having the presumed formula C₁₆ H₁₇ N₅ gave:

    ______________________________________                                                    C          H      N                                                 ______________________________________                                         Calculated                                                                               (%):   68.78        6.13 25.07                                       Found     (%):   68.81        6.05 25.20                                       ______________________________________                                    

EXAMPLES 2-107

Examples 2-107 were achieved according to the process for the preparation as described in Example 1 (1) via isothiourea derivatives. Tables 7 and 8 show respectively melting point, yield (%) and elementary analysis of the resulting isothiourea derivatives and the compounds of this invention.

In Table 7, the general formula: ##STR8## represents the formula wherein p is O and Y is methylthio group in the formula (V) hereinbefore mentioned.

In Table 8, the general formula: ##STR9## represents the formula wherein p is O in the formula (I).

                                      TABLE 7                                      __________________________________________________________________________      ##STR10##                                                                                                          Elementary Analysis                                           Melting          Upper line: Calcd.                                            Point    Molecular                                                                              Lower line: Found                         Ex.                                                                                 A         B    (°C.)                                                                        Yield                                                                              Formula  C  H  N                                  __________________________________________________________________________     (Part I)                                                                           ##STR11##                                                                               2-pyridyl                                                                             166-168                                                                             63.5                                                                               C.sub.16 H.sub.16 N.sub.4 S                                                            64.83 64.87                                                                       5.44 5.26                                                                         18.90 19.01                         3                                                                                  ##STR12##                                                                               2-pyridyl                                                                             148-149                                                                             76.7                                                                               C.sub.16 H.sub. 16 N.sub.4 S                                                           64.83 65.05                                                                       5.44 5.36                                                                         18.90 18.91                         4                                                                                  ##STR13##                                                                               2-pyridyl                                                                             119-120                                                                             71.7                                                                               C.sub.15 H.sub.13 N.sub.4 SCl                                                          56.87 56.60                                                                       4.10 4.09                                                                         17.69 17.05                         5                                                                                  ##STR14##                                                                               2-pyridyl                                                                             205-206                                                                             80.1                                                                               C.sub.15 H.sub.13 N.sub.4 SCl                                                          56.87 56.65                                                                       4.10 3.94                                                                         17.69 17.45                         6                                                                                  ##STR15##                                                                               2-pyridyl                                                                             121-122                                                                             85.5                                                                               C.sub.15 H.sub.13 N.sub.4 SCl                                                          56.87 56.79                                                                       4.10 4.06                                                                         17.69 17.50                         7                                                                                  ##STR16##                                                                               2-pyridyl                                                                             118-119                                                                             55.3                                                                               C.sub.15 H.sub.12 N.sub.4 SCl.sub.2                                                    51.28 51.09                                                                       3.42 3.29                                                                         15.95 15.62                         8                                                                                  ##STR17##                                                                               2-pyridyl                                                                             126-128                                                                             64.5                                                                               C.sub.16 H.sub.16 N.sub.4 OS                                                           61.53 61.43                                                                       5.16 4.98                                                                         17.94 17.47                         9                                                                                  ##STR18##                                                                               2-pyridyl                                                                             162-163                                                                             84.0                                                                               C.sub.16 H.sub.16 N.sub.4 OS                                                           61.53 61.90                                                                       5.16 5.03                                                                         17.94 17.79                         10                                                                                 ##STR19##                                                                               2-pyridyl                                                                             151-152                                                                             70.0                                                                               C.sub.16 H.sub.16 N.sub.4 OS                                                           61.53 61.60                                                                       5.16 5.05                                                                         17.94 18.08                         11                                                                                 ##STR20##                                                                               2-pyridyl                                                                             155-156                                                                             88.0                                                                               C.sub.17 H.sub.18 N.sub.4 O.sub.2 S                                                    59.64 59.76                                                                       5.30 5.24                                                                         16.37 16.77                         (Part II)                                                                      12                                                                                 ##STR21##                                                                               2-pyridyl                                                                             117-118                                                                             86.5                                                                               C.sub.17 H.sub.18 N.sub.4 OS                                                           62.56 63.05                                                                       5.56 5.42                                                                         17.17 17.23                         13                                                                                 ##STR22##                                                                               2-pyridyl                                                                             138-139                                                                             87.5                                                                               C.sub.18 H.sub.20 N.sub.4 OS                                                           63.51 63.54                                                                       5.92 5.84                                                                         16.46 15.96                         14                                                                                 ##STR23##                                                                               2-pyridyl                                                                             103-104                                                                             68.8                                                                               C.sub.16 H.sub.16 N.sub.4 S.sub.2                                                      58.53 58.71                                                                       4.91 4.69                                                                         17.07 17.41                         15                                                                                 ##STR24##                                                                               2-pyridyl                                                                             139-140                                                                             71.1                                                                               C.sub.16 H.sub.16 N.sub.4 O.sub.2 S.sub.2                                              53.33 53.14                                                                       4.48 4.19                                                                         15.55  15.43                        16                                                                                 ##STR25##                                                                               2-pyridyl                                                                             163-164                                                                             68.1                                                                               C.sub.16 H.sub.13 N.sub.4 F.sub.3 S                                                    54.86 54.88                                                                       3.74 3.76                                                                         16.00 16.12                         17                                                                                 ##STR26##                                                                                ##STR27##                                                                            182-183                                                                             65.5                                                                               C.sub.15 H.sub.14 N.sub.4 OS                                                           60.40 60.73                                                                       4.70 4.58                                                                         18.79 18.82                         18                                                                                 ##STR28##                                                                               2-pyridyl                                                                             116-118                                                                             70.0                                                                               C.sub.13 H.sub.12 N.sub.4 OS                                                           57.33 57.50                                                                       4.44 4.18                                                                         20.57 20.54                         19                                                                                 ##STR29##                                                                               2-pyridyl                                                                             104-106                                                                             56.0                                                                               C.sub.13 H.sub.12 N.sub.4 S.sub.2                                                      54.13 54.43                                                                       4.19 4.18                                                                         19.43 19.72                         20                                                                                 ##STR30##                                                                               2-pyridyl                                                                             140-143                                                                             73.3                                                                               C.sub.15 H.sub.20 N.sub.4 S                                                            62.46 62.82                                                                       6.98 6.99                                                                         19.43 19.20                         21                                                                                 ##STR31##                                                                                ##STR32##                                                                            150-152                                                                             46.3                                                                               C.sub.16 H.sub.15 N.sub.3 S                                                            68.29 68.30                                                                       5.38 5.52                                                                         14.94 14.87                         22                                                                                 ##STR33##                                                                               2-pyridyl                                                                             152-153                                                                             60.1                                                                               C.sub.17 H.sub.18 N.sub.4 OS                                                           62.56 62.90                                                                       5.56 5.57                                                                         17.17 17.11                         __________________________________________________________________________      ##STR34##

EXAMPLE 108

Five grams (0.018 mol) of N-cyano-N'-[α-(2-pyridyl)benzyl]-S-methylisothiourea and 5 g (0.057 mol) of N,N-dimethylethylenediamine were dissolved in 100 ml of ethanol, and the whole was reacted under reflux for 10-15 hours. The reaction solution was concentrated under a reduced pressure. The residue was washed with water, followed by recrystalizing from ethyl acetate to produce 3.4 g of N-cyano-N'-(2-dimethylamino)-ethyl-N-[α-(2-pyridyl) benzyl] guanidine (yield: 58.7%).

Melting point 142°-4° C.

Elementary analysis (%) for C₁₈ H₂₂ N₆ :

    ______________________________________                                                  C           H      N                                                  ______________________________________                                         Calculated:                                                                               67.04         6.89   26.07                                          Found:     67.09         6.97   25.96                                          ______________________________________                                    

EXAMPLES 109-123

The following Table 9 shows the compounds which were prepared using the procedures similar to Example 108.

In Table 9 Part I, the general formula: ##STR35## represents the formula wherein A is phenyl, B is pyridyl, and p is 0 in the formula (I) hereinbefore mentioned.

In Table 9 Part II, the general formula: ##STR36## represents the formula wherein A is phenyl, B is pyridyl, and p is 1 in the formula (I).

                                      TABLE 9                                      __________________________________________________________________________       #STR37##                                                                                                             Elementary Analysis                                             Melting        Upper line: Calcd.                                              Point    Molecular                                                                            Lower line: Found                      Ex.   B        R         (°C.)                                                                        Yield                                                                              Formula                                                                               C   H  N                              __________________________________________________________________________     (Part I, No. 1)                                                                109   2-pyridyl                                                                              ##STR38##  151-152                                                                             82.5                                                                               C.sub.20 H.sub.26 N.sub.6                                                            68.53 68.76                                                                        7.49 7.56                                                                         23.98 23.97                     110   2-pyridyl                                                                              ##STR39##  143  86.0                                                                               C.sub.19 H.sub.24 N.sub.6                                                            67.83 67.87                                                                        7.19 7.47                                                                         24.98 24.11                     111   2-pyridyl                                                                              ##STR40##  84-85                                                                               58.0                                                                               C.sub.21 H.sub.28 N.sub.6                                                            69.18 69.21                                                                        7.76 7.81                                                                         23.06 22.89                     112   2-pyridyl                                                                              ##STR41##  136-137                                                                             67.5                                                                               C.sub.21 H.sub.26 N.sub.6                                                            69.58 70.15                                                                        7.23 7.44                                                                         23.19 23.17                     113   2-pyridyl                                                                              ##STR42##  142-143                                                                             75.8                                                                               C.sub.21 H.sub.26 N.sub.6 O                                                          66.64 67.07                                                                        6.92 6.97                                                                         22.21 22.72                     114   3-pyridyl                                                                              ##STR43##  97-98                                                                               64.8                                                                               C.sub.21 H.sub.28 N.sub.6                                                            69.19 69.24                                                                        7.74 7.70                                                                         23.06 23.12                     115   3-pyridyl                                                                              ##STR44##  148-150                                                                             58.1                                                                               C.sub.21 H.sub.21 N.sub.6                                                            69.58 69.36                                                                        7.23 7.22                                                                         23.19 23.51                     116   4-pyridyl                                                                              ##STR45##  133-135                                                                             51.1                                                                               C.sub.21 H.sub.28 N.sub.6                                                            69.19 69.12                                                                        7.74 7.87                                                                         23.06 23.01                     (Part I, No. 2)                                                                117   4-pyridyl                                                                              ##STR46##  166-168                                                                              44.05                                                                             C.sub.21 H.sub.21 N.sub.6                                                            69.58 69.80                                                                        7.23 7.12                                                                         23.19 23.24                     118   2-pyridyl                                                                              ##STR47##  155-158                                                                             73.0                                                                               C.sub.20 H.sub.24 N.sub.6                                                            68.92 69.36                                                                        6.96 7.02                                                                         24.12 24.12                     119   2-pyridyl                                                                              ##STR48##   99-101                                                                             72.6                                                                               C.sub.23 H.sub.30 N.sub.6                                                            70.72 70.87                                                                        7.76 7.58                                                                         21.52 21.11                     __________________________________________________________________________      ##STR49##                                                                                                             Elementary Analysis                                             Melting        Upper line: Calcd.                                              Point    Molecular                                                                             Lower line: Found                     Ex.                                                                               B      R       X      (°C.)                                                                        Yield                                                                              Formula                                                                               C   H  N                              __________________________________________________________________________     (Part II)                                                                      120                                                                               2-pyridyl                                                                            ##STR50##                                                                               CH.sub.2                                                                              104-105                                                                             41.0                                                                               C.sub.22 H.sub.30 N.sub.6                                                            69.81 69.75                                                                        7.99 7.90                                                                         22.20 22.08                     121                                                                               2-pyridyl                                                                            ##STR51##                                                                               CH.sub.2                                                                              136-138                                                                             40.8                                                                               C.sub.22 H.sub.23 N.sub.6                                                            70.18 70.38                                                                        7.50 7.63                                                                         22.32 22.46                     122                                                                               2-pyridyl                                                                            ##STR52##                                                                               (CH.sub.2).sub.2 S                                                                    94-95                                                                               47.1                                                                               C.sub.23 H.sub.32 N.sub.6 S                                                          65.06 65.23                                                                        7.60 7.54                                                                         19.79 19.85                     123                                                                               2-pyridyl                                                                            ##STR53##                                                                               (CH.sub.2).sub.2 S                                                                    130-131                                                                             41.9                                                                               C.sub.23 H.sub.30 N.sub.6 S                                                          65.37 65.48                                                                        7.16 7.36                                                                         19.89 19.11                     __________________________________________________________________________ 

What is claimed is:
 1. A cyanoguanidine derivative of the formula: ##STR54## wherein A represents phenyl; phenyl substituted by lower alkyl, lower alkenyl, halogen, lower alkoxy, lower alkylthio, lower alkylsulfonyl or halo lower alkyl; furyl; thienyl or cycloalkyl of 5 to 6 carbon atoms;B represents pyridyl or pyridine-N-oxide; R represents lower alkyl or lower alkenyl; X represents lower alkylene or lower alkylene having a terminal sulfur atom; and p is 0 or 1, with the proviso that (i) when A is unsubstituted phenyl, B is pyridine-N-oxide and (ii) when A is unsubstituted phenyl and B is pyridine-N-oxide, p is 0, or a pharmaceutically acceptable acid addition salt thereof.
 2. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR55## or a pharmaceutically acceptable acid addition salt thereof.
 3. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR56## or a pharmaceutically acceptable acid addition salt thereof.
 4. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR57## or a pharmaceutically acceptable acid addition salt thereof.
 5. A cyanoguanidine derivative as claimed in claim 1, represented by the formula ##STR58## or a pharmaceutically acceptable acid addition salt thereof.
 6. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR59## or a pharmaceutically acceptable acid addition salt thereof.
 7. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR60## or a pharmaceutically acceptable acid addition salt thereof.
 8. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR61## or a pharmaceutically acceptable acid addition salt thereof.
 9. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR62## or a pharmaceutically acceptable acid addition salt thereof.
 10. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR63## or a pharmaceutically acceptable acid addition salt thereof.
 11. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR64## or a pharmaceutically acceptable acid addition salt thereof.
 12. A cyanoguanidine derivative as claimed in claim 1, represented by the formula: ##STR65## or a pharmaceutically acceptable acid addition salt thereof. 